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- Institut für Physik (17)
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- Institut für Mathematik und Informatik (4)
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In this thesis we have revisited the formation of the excitonic insulator (EI), which realizes an exciton condensate. In contrast to optically created exciton condensates, the EI forms in thermal equilibrium and is solely driven by the Coulomb attraction between electrons and holes. The EI phase is anticipated to occur near the semimetal-semiconductor (SM-SC) transition at low temperatures. Depending from which side the EI is approached, it forms due to a BCS-type condensation of electron-hole pairs or a Bose-Einstein condensation (BEC) of excitons. The extended Falicov-Kimball model (EFKM) is the minimal model the EI can be described with. This model describes spinless fermions in two dispersive bands (f band and c band), that interact via a local Coulomb repulsion. The EFKM is also used to describe electronic ferroelectricity (EFE). Both phases, the EI and EFE-type ordering, are characterized by a spontaneous f-c hybridization in the EFKM. We have presented the EI phase, the EFE phase, and the orderings they compete with. Moreover, we have determined the ground-state phase diagram of the EFKM. We have focused particularly on the anticipated BCS-BEC crossover within the EI and have analyzed the formation scenarios. The exciton spectrum and the exciton density in the normal phase close to the critical temperature give information about relevant particles and therefore the nature of the transition. We have demonstrated that the whole EI is surrounded by a halo", that is, a phase composed of electrons, holes and excitons. However, on the SM side, only excitons with a finite momentum exist. These excitons appear only in a small number and barely influence the SM-EI transition. This phase transition is driven by critical electron-hole fluctuations, generated by electrons and holes at the Fermi surface. On the SC side, excitons with arbitrary momenta exist. Most notably, we have found the number of zero-momentum excitons to diverge at the SC-EI transition, signaling the BEC of these particles. Within the EI phase, there is a smooth crossover from the BCS regime to the BEC regime. One of the promising candidates to observe the EI experimentally, is the transition-metal dichalcogenide 1T-TiSe2. Strong evidences were found favoring an EI scenario of the charge-density-wave (CDW) formation in this material. However, some aspects point to a lattice instability to drive the CDW transition. We have addressed this issue by analyzing the recently discovered chiral property of the CDW in 1T-TiSe2. We have found that the EI scenario is insufficient to explain a stable, long range chiral charge ordering. Lattice degrees of freedom must be taken into account. In particular, nonlinear electron-phonon coupling and phonon-phonon interaction are crucial. By estimating appropriate model parameters for 1T-TiSe2, we have suggested a combination of excitonic and lattice instability to drive the CDW transition in this material. Experiments in 1T-TiSe2 and other materials suggest that the coupling to the lattice is non-negligible. We have extended therefore the model by an explicit exciton-phonon interaction, and have analyzed crucial effects of this interaction. While the single-particle spectrum is not modified qualitatively, the electron-hole pair spectrum changes significantly. The inclusion of the phonons lead to a massive collective mode in the ordered ground state in contrast to the case for vanishing exciton-phonon coupling, where the mode is acoustic. We have suggested that a gapless collective mode leads to off-diagonal long range order. This questions that the ground state for finite exciton-phonon coupling represents a condensate.
The region surrounding the excitonic insulator phase is a three-component plasma composed of electrons, holes, and excitons. Due to the extended nature of the excitons, their presence influences the surrounding electrons and holes. We analyze this correlation. To this end, we calculate the density of bound electrons, the density of electrons in the correlated state, the momentum-resolved exciton density, and the momentum-resolved density of electron-hole pairs that are correlated but unbound. We find qualitative differences in the electron-hole correlations between the weak-coupling and the strong-coupling regime.
Abstract
The presented experimental system is a barrier discharge system with plane parallel electrodes. The lateral surface charge distribution being deposited on the dielectric layer during each breakdown is observed optically using the well known electro-optic effect (Pockels effect). The temporal resolution of the surface charge measurement has been increased to 200 ns, and so for the first time it is possible to resolve the charge transfer to the dielectric surface in a single breakdown. In the present measurements, a patterned glow-like barrier discharge is investigated. It is found that the charge reversal in a single discharge spot (microdischarge) starts in the centre and then grows outwards. These experimental findings verify previously unconfirmed predictions from earlier numerical calculations and thereby contribute to a better understanding of the interaction between the plasma and the electrical charge on the electrodes.
In the PhD-thesis a conditional random field approach and its implementation is presented to predict the interaction sites of protein homo- and heterodimers using the spatial structure of one protein partner from a complex. The method includes a substantially simple edge feature model. A novel node feature class is introduced that is called -change in free energy-. The Online Large-Margin algorithm is adapted in order to train the model parameters given a classified reference set of proteins. A significantly higher prediction accuracy is achieved by combining our new node feature class with the standard node feature class relative accessible surface area. The quality of the predictions is measured by computing the area under the receiver operating characteristic.
Inflammation is part of the body's immune response in order to remove harmful stimuli—like pathogens, irritants or damaged cells—and start the healing process. Recurrent or chronic inflammation on the other side seems a predisposing factor for carcinogenesis and has been found associated with cancer development. In chronic pancreatitis mutations of the cationic trypsinogen (PRSS1) gene have been identified as risk factors of the disease. Hereditary pancreatitis (HP) is a rare cause of chronic pancreatic inflammation with an early onset, mostly during childhood. HP often starts with recurrent episodes of acute pancreatitis and the clinical phenotype is not very much different from other etiologies of the disease. The long-lasting inflammation however generates a tumor promoting environment and represents a major risk factor for tumor development This review will reflect our knowledge concerning the specific risk of HP patients to develop pancreatic cancer.
Purines of exogenous and endogenous sources are degraded to uric acid in human beings. Concentrations >6.8 mg uric acid/dl serum cause hyperuricemia and its symptoms. Pharmaceuticals and the reduction of the intake of purine-rich food are used to control uric acid levels. A novel approach to the latter proposition is the enzymatic reduction of the purine content of food by purine-degrading enzymes. Here we describe the production of recombinant guanine deaminase by the yeast Arxula adeninivorans LS3 and its application in food. In media supplemented with nitrogen sources hypoxanthine or adenine, guanine deaminase (AGDA) gene expression is induced and intracellular accumulation of guanine deaminase (Agdap) protein occurs. The characteristics of the guanine deaminase isolated from wild-type strain LS3 and a transgenic strain expressing the AGDA gene under control of the strong constitutive TEF1 promoter were determined and compared. Both enzymes were dimeric and had temperature optima of 55°C with high substrate specificity for guanine and localisation in both the cytoplasm and vacuole of yeast. The enzyme was demonstrated to reduce levels of guanine in food. A mixture of guanine deaminase and other purine degradation enzymes will allow the reduction of purines in purine-rich foods.
The globally threatened Aquatic Warbler (Acrocephalus paludicola) is the rarest migratory songbird in Europe. Before the population declined dramatically after 1960, the Aquatic Warbler was a common species in European mires and river flood¬plains. Today, the global population is estimated to count 27 600 individuals, of which approx. 90 % are concentrated in only three countries during the breeding season: Belarus, Poland and Ukraine. Despite numerous conservation efforts mainly under¬taken in European countries, the population decline has not been stopped. Although the Aquatic Warbler is considered a “European” bird species because of the location of its breeding grounds, it spends up to six months on migration and on the wintering grounds on the African continent. A comprehensive species conservation strategy must therefore include the preservation of African resting and wintering grounds. This study analyses the ecol¬ogy of Aquatic Warbler in its wintering grounds using the example of the Djoudj National Park area in north-western Senegal. The study aims, first, to close knowledge gaps regarding the behaviour and the habitat requirements of Aquatic Warblers during their stay on the wintering grounds to provide a scientific base for long-term species conservation management; second, to assess the importance of the wintering site in the Djoudj area is in a global perspec¬tive; and third, to identify threats to the Djoudj area as a suitable Aquatic Warbler habitat. In a fourth step, science-based management recommendations are formu¬lated to support the ongoing practical conservation work of the Djoudj National Park administration with regard to the Aquatic Warbler. The main outcomes of the study are the following: (I) We confirmed the presence of Aquatic Warblers in the Djoudj area between mid-December and the end of March. (II) The connection between the wintering ground “Djoudj National Park area” and the breeding ground “Biebrza valley” (eastern Poland) was confirmed by the resighting of a ringed Aquatic Warbler individual. (III) The remiges moult of the species was observed under natural conditions for the first time. We confirmed that the Aquatic Warbler undergoes a complete moult on its wintering grounds, following the typical sequence of passerine moult. (IV) Aquatic Warblers occur in shallowly inundated vegetation with dominant stands of Oryza longistaminata, Eleocharis mutata, Scirpus maritimus, Scirpus litto¬ralis and Sporobulus robustus interspersed with small (1–2 m²) areas of open water. The afore mentioned herbaceous species form a homogenous wetland vegetation of approximately 0.6–1.5 m height, with a coverage of 80 % to 100 %. Wild rice (Oryza longistaminata) may provide the most suitable habitat conditions as suggested by the very high density of Aquatic Warblers at sites dominated by this species. Preferential habitat may include a few solitary trees, but open woodland or scrublands are unsuit-able for Aquatic Warbler. Pure stands of cattail (Typha australis) are avoided. The water level in the habitat areas varies between 0 (humid soil) and 40 cm above the ground. Constant inundation seems to be essential, as Aquatic Warblers were never encountered in dry parts of the study area. All known Aquatic Warbler habitats in the study area are influenced by brackish or salty water. (V) During winter Aquatic Warblers use a home range of 3.9 ha (± 1.9) in aver¬age, which is shared with other individuals and species. No territorial behaviour was observed in the winter quarters. (VI) The vegetation and land cover map prepared distinguishes six classes of her¬baceous vegetation and five general land cover classes. (VII) There are 4 729 ha of potential Aquatic Warbler habitat within the study area. (VIII) We estimate the density of the Aquatic Warbler population in the study area to range between 0 and 2.26 individuals per hectare with a total population size of 776 individuals, or 260–4 057 individuals in a 95 % credibility interval. Hence we conclude that 1.1–3.8 % (0.37–19.8 % within the 95 % credibility interval) of the global Aquatic Warbler wintering population are found in the Djoudj area. (VIII) The Aquatic Warbler habitats in the Djoudj area are affected by the inun¬dation regime, water circulation, changes in salinity, grazing, the spread of cattail (Typha australis), the encrustation of vegetation, the protection status of passerine migrator habitats and the expansion of rice cultivation a. Our management proposals for the preservation of existing and the development of new Aquatic Warbler habitats were formulated and incorporated into the Management Plan of the Djoudj National Park 2014–2018.
Chemistry and biology of Phenolics isolated from Myricaria germanica (L.) Desv. (Tamaricaceae)
(2014)
In accordance with the recent worldwide interest in plant phenolics, which emerges from their broad range of biological activities, particular emphasis has been focused, in the present thesis, on the constitutive phenolics of the extract of Myricaria germanica (L.) Desv. (Tamaricaceae). During the current thesis twenty phenolics (1 – 20) were isolated and identified from the aqueous/ethanol extract of the whole Myricaria germanica plant. The isolates include four hitherto unknown natural phenolics (2, 10, 12 and 20). Also, the cytotoxic activities of M. germanica extract, column fractions, and one new natural isolate against three different solid tumor cell lines, namely, breast cancer (MCF-7), prostate (PC-3), and liver (Huh-7) cancer cell using SRB viability assay have been investigated and first insights into mode of action have been obtained.
Staphylococcus aureus is a human pathogen that can cause a wide range of diseases. Although formerly regarded as extracellular pathogen, it has been shown that S. aureus can also be internalized by host cells and persist within these cells. In the present study, we comparatively analyzed survival and physiological adaptation of S. aureus HG001 after internalization by two human lung epithelial cell lines (S9 and A549), and human embryonic kidney cells (HEK 293). Combining enrichment of bacteria from host-pathogen assays by cell sorting and quantitation of the pathogen's proteome by mass spectrometry we characterized S. aureus adaptation during the initial phase between 2.5 h and 6.5 h post-infection. Starting with about 2 × 106 bacteria, roughly 1450 S. aureus proteins, including virulence factors and metabolic enzymes were identified by spectral comparison and classical database searches. Most of the bacterial adaptation reactions, such as decreased levels of ribosomal proteins and metabolic enzymes or increased amounts of proteins involved in arginine and lysine biosynthesis, enzymes coding for terminal oxidases and stress responsive proteins or activation of the sigma factor SigB were observed after internalization into any of the three cell lines studied. However, differences were noted in central carbon metabolism including regulation of fermentation and threonine degradation. Since these differences coincided with different intracellular growth behavior, complementary profiling of the metabolome of the different non-infected host cell types was performed. This revealed similar levels of intracellular glucose but host cell specific differences in the amounts of amino acids such as glycine, threonine or glutamate. With this comparative study we provide an impression of the common and specific features of the adaptation of S. aureus HG001 to specific host cell environments as a starting point for follow-up studies with different strain isolates and regulatory mutants.
Staphylococcus aureus is a commensal that colonizes the skin and mucosa of 20-30% of the human population without leading to symptoms of diseases. However, it is also the most important cause of nosocomial infections. Those range from minor skin infections to life-threatening diseases such as pneumonia, endocarditis or septicaemia. Development of strains with resistance against many antibiotics complicates the situation further. The variety of strains with their various properties is one reason why no successful vaccine has been introduced to the market, yet. Therefore, efficient strategies for prevention and therapy of these dangerous infections are urgently needed. To accomplish these goals, the understanding of molecular interactions between host and pathogen is indispensable. Within this dissertation, several internalization experiments were performed aiming to investigate the interaction of S. aureus HG001 and human cell lines upon infection on the protein level. In order to obtain sufficient amounts of proteins for comprehensive physiological interpretations, it is necessary to enrich bacteria, secreted bacterial proteins or infected host cells upon internalization. In the framework of this thesis, bacteria which continuously produce green fluorescent protein (GFP) were employed. With that it was possible to sort bacteria from lysed host cells by flow cytometry or to separate host cells carrying bacteria after contact from those which did not. Subsequently, the proteins were proteolytically digested and peptides were analyzed by mass spectrometry in a gel-free proteomics approach. To allow such analyses also for staphylococci which do not produce GFP, such as clinical isolates, an additional protocol was developed. Prior to the infection, bacteria were labeled with fluorescent or para-magnetic nanoparticles. Afterwards bacteria could be separated from host cell debris by fluorescence-based cell sorting or with the help of a strong magnet. In order to cover also important secreted virulence factors of S. aureus HG001, phagosomes and engulfed bacteria and secreted proteins were isolated from infected host cells. Further steps of protocol optimization included improved bacterial cell counting by fluorescence-based flow cytometry, enhanced data analysis by combination of different search algorithms, and comprehensive functional annotation of proteins of the applied strain by sequence comparison with other strains and organisms. First, the proteome adaptation of internalized S. aureus HG001 and the infected A549 host cells was investigated during the first hours of infection. It became clear, that the bacteria replicate inside the host during the first 6.5 h. After internalization the levels of bacterial enzymes involved in protein biosynthesis decreased. Furthermore, bacteria adapted their proteome to the harsh intracellular conditions such as oxygen limitation, cell wall stress, host defense in terms of oxidative stress, and nutrient limitation. After contact to S. aureus HG001, A549 cells produced increased amounts of cytokines (e.g. IL-8, IFN-γ) in comparison to non-treated A549 cells. In addition, activation of the immunoproteasome and hints of early apoptosis activity were observed. Afterwards, the response of S. aureus HG001 to internalization by A549, S9 or HEK 293 cells was compared on the proteome level. It was obvious, that the adaptation to stress and the reduced protein synthesis are conserved mechanisms. Host dependent differences were detected especially in the energy metabolism and the synthesis of some amino acids. Additionally, bacteria showed different intracellular replication patterns depending on the host cell line. A higher percentage of extracellular bacterial proteins was found in isolated phagosomes compared to the sorted samples. Selected low abundant virulence factors could be quantified at two points in time after infection with the help of the sensitive single reaction monitoring (SRM) method. Further, a heterogeneous mixture of several phagosomal maturation steps was present during the first 6.5 h after infection. Finally, the gel-free proteome analyses could be applied to investigate Bordetella pertussis, the cause of whooping cough, during iron limitation and after internalization, and the results were compared to the S. aureus HG001 data.
Magnetic reconnection is a ubiquitous phenomenon observed in a wide range of magnetized plasmas from magnetic confinement fusion devices to space plasmas in the magnetotail. The process enables the release of accumulated magnetic energy by rapid changes in magnetic topology, heating the plasma in the vicinity of the reconnection site, generating fast particles and allowing a wealth of instabilities to grow. This thesis reports on the results from a newly constructed linear, cylindrical and modular guide field reconnection experiment with highly reproducible events, VINETA.II. A detailed analysis of the reconnecting current sheet properties on a macroscopic and microscopic scale in time and space is presented. In the experiment, four parallel axial wires create a figure-eight in-plane magnetic field with an X-line along the central axis, as well as an axial inductive field that drives magnetic reconnection. Particle-in-cell simulations show that the axial current is limited by sheaths at the boundaries and that electrostatic fields along the device axis always set up in response to the induced electric field. Current sheet formation requires an additional electron current source, realized as a plasma gun, which discharges into a homogeneous background plasma created by a rf antenna. The evolution of the plasma current is found to be dominantly set by its electrical circuit. The current response to the applied electric field is mainly inductive, which in turn strongly influences the reconnection rate. The three-dimensional distribution of the current sheet is determined by the magnetic mapping of the plasma gun along the sheared magnetic field lines, as well as by radial cross-field expansion. This expansion is due to a lack of equilibrium in the in-plane force balance. Resistive diffusion of the magnetic field by E=η j is found to be by far insufficient to account for the high reconnection rate E=-dΨ/dt at the X-line, indicating the presence of large electrostatic fields which do not contribute to dissipative reconnection. High-frequency magnetic fluctuations are observed throughout the current sheet which are compared to qualitatively similar observations in the Magnetic Reconnection Experiment (MRX, Princeton). The turbulent fluctuation spectra in both experiments display a spectral kink near the lower hybrid frequency, indicating the presence of lower hybrid type instabilities. In contrast to the expected perpendicular propagation of mainly electrostatic waves, an electromagnetic wave is found in VINETA.II that propagates along the guide field and matches the whistler wave dispersion. Good correlation is observed between the local axial current density and the fluctuation amplitude across the azimuthal plane. Instabilities driven by parallel drifts can be excluded due to the large required drift velocities or low resulting phase velocities that are not observed. It is instead suggested that a perpendicular, electrostatic lower hybrid mode indeed exists that resonantly excites a parallel, electromagnetic whistler wave through linear mode conversion. The resulting fluctuations are found to be intrinsic to the localized current sheet and are independent of the slower reconnection dynamics. Their amplitude is small compared to the in-plane fields, and have a negligible contribution to anomalous resistivity through momentum transport in the present parameter regime.
High-throughput expression data have become the norm in molecular biology research. However, the analysis of expression data is statistically and computationally challenging and has not kept up with their generation. This has resulted in large amounts of unexplored data in public repositories. After pre-processing and quality control, the typical gene expression analysis workflow follows two main steps. First, the complexity of the data is reduced by removing the genes that are redundant or irrelevant for the biological question that motivated the experiment, using a feature selection method. Second, relevant genes are investigated to extract biological information that could aid in the interpretation of the results. Different methods, such as functional annotation, clustering, network analysis, and/or combinations thereof are useful for the latter purpose. Here, I investigated and presented solutions to three problems encountered in the expression data analysis workflow. First, I worked on reducing complexity of high-throughput expression data by selecting relevant genes in the context of the sample classification problem. The sample classification problem aims to assign unknown samples into one of the known classes, such as healthy and diseased. For this purpose, I developed the relative signal-to-noise ratio (rSNR), a novel feature selection method which was shown to perform significantly better than other methods with similar objectives. Second, to better understand complex phenotypes using high-throughput expression data, I developed a pipeline to identify the underlying biological units, as well as their interactions. These biological units were assumed to be represented by groups of genes working in synchronization to perform a given function or participate in common biological processes or pathways. Thus, to identify biological units, those genes that had been identified as relevant to the phenotype under consideration through feature selection methods were clustered based on both their functional annotations and expression profiles. Relationships between the associated biological functions, processes, and/or pathways were investigated by means of a co-expression network. The developed pipeline provides a new perspective to the analysis of high-throughput expression data by investigating interactions between biological units. Finally, I contributed to a project where a network describing pluripotency in mouse was used to infer the corresponding network in human. Biological networks are context-specific. Combining network information with high-throughput expression data can explain the control mechanisms underlying changes and maintenance of complex phenotypes. The human network was constructed on the basis of orthology between mouse and human genes and proteins. It was validated with available data in the literature. The methods and strategies proposed here were mainly trained and tested on microarray expression data. However, they can be easily adapted to next-generation sequencing and proteomics data.
Approaches to the Analysis of Proteomics and Transcriptomics Data based on Statistical Methodology
(2014)
Recent developments in genomics and molecular biology led to the generation of an enormous amount of complex data of different origin. This is demonstrated by a number of published results from microarray experiments in Gene Expression Omnibus. The number was growing in exponential pace over the last decade. The challenge of interpreting these vast amounts of data from different technologies led to the development of new methods in the fields of computational biology and bioinformatics. Researchers often want to represent biological phenomena in the most detailed and comprehensive way. However, due to the technological limitations and other factors like limited resources this is not always possible. On one hand, more detailed and comprehensive research generates data of high complexity that is very often difficult to approach analytically, however, giving bioinformatics a chance to draw more precise and deeper conclusions. On the other hand, for low-complexity tasks the data distribution is known and we can fit a mathematical model. Then, to infer from this mathematical model, researchers can use well-known and standard methodologies. In return for using standard methodologies, the biological questions we are answering might not be unveiling the whole complexity of the biological meaning. Nowadays it is a standard that a biological study involves generation of large amounts of data that needs to be analyzed with a statistical inference. Sometimes data challenge researchers with low complexity task that can be performed with standard and popular methodologies as in Proteomic analysis of mouse oocytes reveals 28 candidate factors of the "reprogrammome". There, we established a protocol for proteomics data that involves preprocessing of the raw data and conducting Gene Ontology overrepresentation analysis utilizing hypergeometric distribution. In cases, where the data complexity is high and there are no published frameworks a researcher could follow, randomization can be an approach to exploit. In two studies by The mouse oocyte proteome escapes maternal aging and CellFateScout - a bioinformatics tool for elucidating small molecule signaling pathways that drive cells in a specific direction we showed how randomization can be performed for distinct complex tasks. In The mouse oocyte proteome escapes maternal aging we constructed a random sample of semantic similarity score between oocyte transcriptome and random transcriptome subset of oocyte proteome size. Therefore, we could calculate whether the proteome is representative of the trancriptome. Further, we established a novel framework for Gene Ontology overrepresentation that involves randomization testing. Every Gene Ontology term is tested whether randomly reassigning all gene labels of belonging to or not belonging to this term will decrease the overall expression level in this term. In CellFateScout - a bioinformatics tool for elucidating small molecule signaling pathways that drive cells in a specific direction we validated CellFateScout against other well-known bioinformatics tools. We stated the question whether our plugin is able to predict small molecule effects better in terms of expression signatures. For this, we constructed a protocol that uses randomization testing. We assess here if the small molecule effect described as a (set of) active signaling pathways, as detected by our plugin or other bioinformatics tools, is significantly closer to known small molecule targets than a random path.
The dentate gyrus (DG) of the hippocampus is one of the stem cell housing niches in the adult mammalian brain. Canonical Wingless-type (Wnt) signals provided by the microenvironment are one of the major niche factors that regulate the differentiation of adult neural stem cells (aNSCs) towards the neuronal lineage. Wnts are part of a complex and diverse set of signaling pathways with a wide range of possible interactions. It remains unknown whether different canonical and non-canonical Wnt signals act in a stage-specific manner to regulate distinctive steps of adult hippocampal neurogenesis. Using in vitro assays on adult hippocampal NSCs, we identified an attenuation of canonical Wnt/ß-Catenin signaling responsiveness in the course of neuronal differentiation, while non-canonical Wnt/Planar Cell Polarity (PCP) signaling events progressively increased. Single-cell genetic manipulations were performed by using retroviral vectors to target dividing progenitor cells in the murine hippocampus. Retrovirus-mediated knockdown of ATP6AP2, a recently discovered core protein involved in both Wnt signaling pathways, revealed that the dual role of this adaptor protein is dependent on the signaling context that is present. We were able to confirm its dual role in neurogenic Wnt signaling in cultured adult hippocampal progenitors (AHPs) for both canonical Wnt signaling in proliferating AHPs and non-canonical Wnt signaling in differentiating AHPs. Specific knockdown of ATP6AP2 in neural progenitor cells in vivo resulted in a decreased induction of neuronal cell fate and severe morphological defects of newborn neurons, likely via altering both canonical and non-canonical Wnt signaling. Furthermore, in vivo knockdown of PCP core proteins CELSR1-3 and FZD3 mimicked the maturational defects of ATP6AP2-deficient neuroblasts but did not affect granule cell fate. In summary, the data presented here characterize a transition of Wnt signaling responsiveness from Wnt/ß-Catenin signaling to non-canonical Wnt/PCP signaling in the course of granule cell fate that was confirmed in a human pluripotent stem cell (hPSC)-based model of dentate granule neurogenesis. Our findings suggest that these pathways show stage-dependent activities and regulate distinct steps of adult dentate granule cell neurogenesis. Conclusively, we provide evidence for a stage-specific regulation of fate determination through the Wnt/ß-Catenin pathway and granule cell morphogenesis through the Wnt/PCP signaling pathway, including the FZD3-CELSR1-3 system. Additionally, the Wnt adaptor protein ATP6AP2 is involved in earlier and later stages of adult neurogenesis and its knockdown in vivo resembles all phenotypic features of both canonical and Wnt/PCP signaling mutants.
The present thesis deals with dynamic structures that form during the expansion of plasma into an environment of much lower plasma density. The electron expansion, driven by their pressure, occurs on a much faster time scale than the ion expansion, owed to their mobility. The high inertia of the ions causes the generation of an ambipolar electric field that decelerates the escaping electrons while accelerating the ions. The ambipolar boundary propagates outwards and forms a plasma density front. For a small density differences, the propagation of the front can be described with the linear ansatz for ion acoustic waves. For a large density differences, experiments have shown that the propagation velocity of such a front is still related to the ion sound velocity. However, the reported proportionality factors are scattered over a wide range of values, depending on the considered initial and boundary conditions. In this thesis, the dynamics during plasma expansion are studied with the use of experiments and a versatile particle-in-cell simulation. The experimental investigations are performed in the linear helicon device Piglet. The experiment features a fast valve, which is used to shape the neutral gas density profile. During the pulsed rf-discharges, plasma is generated in the source region and expands collisionless into the expansion chamber. The computer simulation is tailored very close to the experiment and provides a deeper insight in the particle kinetics. The experimental results show the existence of a propagating ion front. Its velocity is typically supersonic and depends on the density ratio of the two plasmas. The ion front features a strong electric field. The front can have similar properties to a double layer is not necessarily a double layer by definition. The computer simulation reveals that the propagating electric field repels the downstream ambient ions. These ions form a stream with velocities up to twice as high as the front velocity. The observed ion density peak is due to the accumulation of the repelled ions and is located at their turning point. The ion front formation depends strongly on the initial ion density profile and is part of a wave-breaking phenomenon. The observed front is followed by a plateau of little plasma density variation. This could be confirmed for the expansion experiment by a comparison with virtual diagnostics in the computer simulation. The plateau has a plasma density determined by the ratio between the high and low plasma density. It consists of streaming ions that have been accelerated in the edge of the main plasma. The presented results confirm and extend findings obtained by independent numerical models and simulations.
Background: Alcohol dependence is among the most severely stigmatized mental disorders. We examine whether negative stereotypes and illness beliefs related to alcohol dependence have changed between 1990 and 2011. Methods: We used data from two population surveys with identical methodology that were conducted among German citizens aged ≥18 years, living in the ‘old' German states. They were conducted in 1990 and 2011, respectively. In random subsamples (1990: n = 1,022, and 2011: n = 1,167), identical questions elicited agreement with statements regarding alcohol dependence, particularly with regard to the illness definition of alcohol dependence and blame. Results: Overall, agreement with negative stereotypes did not change in the course of 2 decades. About 55% of the respondents agreed that alcohol dependence is an illness like any other, >40% stated that it was a weakness of character and 30% endorsed that those affected are themselves to blame for their problems. Conclusions: It is apparent that promoting an illness concept of alcohol dependence has not been an easy solution to the problem of stigma. We discuss how the normative functions of alcohol dependence stigma might have prevented a reduction of negative stereotypes.
Type 2 diabetes mellitus is one of the most challenging health problems for the next decades. The impact of type 2 diabetes mellitus on health care systems is largely driven by the increasing prevalence, the management of the disease and subsequent comorbidities, even in people with prediabetes or undiagnosed type 2 diabetes mellitus. An early detection of high risk groups is necessary to identify and modify risk factors such as obesity, physical inactivity or cigarette smoking which showed regional disparities in their distribution within a country. This leads to the assumption that there might be regional disparities regarding the prevalence and incidence of type 2 diabetes mellitus as well. For Germany as for other countries, comparable data on possible regional disparities in the prevalence and incidence of type 2 diabetes mellitus are missing. The aim of the present dissertation is to estimate the prevalence and incidence of type 2 diabetes mellitus on regional level within Germany, and to estimate the smoking prevalence as a modifiable risk factor in individuals with type 2 diabetes mellitus using data from the Diabetes Collaborative Research of Epidemiologic Studies consortium (DIAB CORE) within the Competence Net Diabetes in Germany. Well comparable data of five regional studies and one nationwide reference study are included: the Study of Health in Pomerania (SHIP); the Cardiovascular Disease, Living and Ageing in Halle Study (CARLA); the Dortmund Health Study (DHS); the Heinz Nixdorf Recall Study (HNR); the Cooperative Health Research in the Region of Augsburg Study (KORA); and the German National Health Interview and Examination Survey 1998 (GNHIES 98). First, the prevalence of type 2 diabetes mellitus was estimated. Data from five regional population-based studies and one nationwide study conducted between 1997 and 2006 with participants aged 45 to 74 years were analyzed. Type 2 diabetes mellitus prevalence estimates based on self-reports (standardized to the German population for the regional studies, reference date 2007/12/31) were compared. Of 11,688 participants of the regional studies, 1,008 had a known type 2 diabetes mellitus, corresponding to a prevalence of 8.6% (95% confidence interval [CI] 8.1% 9.1%). The standardized prevalence was highest in the East with 12.0% (95% CI 10.3% 13.7%) and lowest in the South of Germany with 5.8% (95% CI 4.9% 6.7%).Second, the incidence of type 2 diabetes mellitus was estimated. Data from participants (baseline age 45 to 74 years) from five regional population-based studies were included. The incidence rates per 1,000 person-years (95% CI) and the cumulative incidence (95% CI) from regional studies were directly standardized to the German population (reference date 2007/12/31) and weighted by inverse probability weights for losses to follow-up. Of 8,787 participants, 521 (5.9%) developed type 2 diabetes mellitus corresponding to an incidence rate of 11.8 per 1,000 person-years (95% CI 10.8 12.9). The incidence of known type 2 diabetes mellitus showed regional disparities within Germany. The incidence was highest in the East and lowest in the South of Germany with 16.9 (95% CI 13.3 21.8) vs. 9.0 (95% CI 7.4 11.1) per 1,000 person-years, respectively. Third, the smoking prevalence in participants aged 20 to 79 years with type 2 diabetes mellitus in the regional SHIP and the nationwide GNHIES 98 was estimated. Prevalence estimates of cigarette smoking were calculated using weights reflecting the European adult population (reference date 2005/12/31). The overall prevalence of current smoking was lower among participants with type 2 diabetes mellitus than among participants without type 2 diabetes mellitus (17.3% vs. 38.0% in SHIP and 24.7% vs. 32.1% in GNHIES 98). In both studies, the prevalence of current smoking was highest in men aged 20 to 39 years, in particular among men with type 2 diabetes mellitus. To conclude, considerable disparities in prevalence and incidence of type 2 diabetes mellitus indicate the need for interventions on the regional level within Germany. Former smoking was more prevalent among both men and women with type 2 diabetes mellitus in comparison to current and non-smoking. This finding probably reflects behavioural changes secondary to the disease onset and medical counselling. The finding that men aged 20 to 39 years with type 2 diabetes mellitus were more often current smokers than men without type 2 diabetes mellitus underpins the importance of smoking as one of the main modifiable risk factors for type 2 diabetes mellitus.
During the past decade, various physical properties of the Yukawa ball, like structure and energy states, were unraveled using experiments. However, the dynamical features served further attention. Therefore, the main aim of my thesis was to investigate and understand how a finite system-represented by Yukawa clusters-evolves from a solid, crystalline structure to a liquid-like system, how it behaves in this phase and in what manner the reordering back into the solid state can be described. As a method of choice to reach this goal, laser heating has been proven successful. Moreover, the special importance of wakefields for dust clusters confined at low neutral gas pressure was addressed. Melting of finite dust clouds can be induced in two ways, either by altering the properties of the ambient plasma or by laser heating. The latter was shown to be a generic melting scenario, allowing to estimate a critical coupling parameter at the melting point. Moreover, the melting transition of finite 3D dust systems was found to be a two-step process where angular order is lost before the radial order starts to diminish at higher energies. Next, the mode dynamics of finite 3D dust ensembles in the solid and the liquid phase was studied. Crystal and fluid modes revealed the main spectral properties of the system. The normal modes are mainly suited to describe crystalline states. Fluid modes were excited naturally and via laser heating, with excitation frequencies almost independent of the coupling parameter in the solid and the liquid-like regime. Tuning the plasma parameters can be used to vary the particle-particle interaction via the ion focus. Both methods, even though assuming equilibrium situations, allowed to hint at these wakefields. The corresponding peaks in the fluid and normal mode spectra were no eigenmodes, confirming the nonequilibrium character of the ion focusing effect. First steps to extend the normal mode theory to achieve the dynamics of wake-affected nonequilibrium dust clusters were presented. Statistical quantities were obtained evaluating long-run experiments and transport coeffcients for finite dust systems were calculated via the instantaneous normal mode technique. Diffusion was found considerably higher for 3D than for 2D dust clusters. Using the configurational entropy, we have shown that in 2D and 3D disorder increases with increasing size of the system, in agreement with simulations. The temperature dependence of the configurational entropy differs for 2D and 3D dust clouds, with a threshold behavior found for finite 2D ensembles only. Finally, using instantaneous normal modes to reveal the total fraction of unstable modes, the predictive connection of Keyes (Phys Rev E 62, p7905, 2000), between transport and disorder was tested and verified for 2D, but not for 3D clusters. The reason for this has to be left open. Finally, laser-mediated recrystallization processes of finite 3D dust clouds were investigated. First, the temporal evolution of the Coulomb coupling parameter was traced during heating and recrystallization. A cooling rate has been determined from the initial phase of recrystallization. This cooling rate is lower than damping by the neutral gas, in agreement with simulations. We have observed a large fraction of metastable states for the final cluster configurations. Further, we have revealed that the time scale for the correlation buildup in the finite 3D ensemble was on even slower scales than cooling. Thus, different time scales can be attributed to the fast emergence of the shells and to the slower individual ordering within the shells.
The soil bacterium Bacillus subtilis is capable of surviving most of the ensuing environmental stress conditions. The dynamic nature of the soil habitat is manifested with varying amounts of nutrients, frequent flooding, drying and variation of other growth parameters like temperature, acidity, aeration etc. In order to survive in these conditions, B. subtilis has evolved to employ very complex adaptational responses. These adaptational responses are often multi-faceted; hence comprehensive understanding of the adaptational responses requires generation and integration of data on multi-omics level. Hence, multi-omics based detailed analysis was performed for the molecules involved in the central carbon metabolism (CCM) and proline biosynthesis pathway. In the current study two major stress conditions were extensively investigated: 1) energy limitation/starvation which is achieved by limiting glucose in the growth medium, 2) osmostress resulting from frequent drying out of soil which is simulated by adding 1.2 M NaCl to the growth medium. In addition to osmostress, the naturally available osmoprotectant glycine betaine (GB) was supplemented to understand the simultaneous influence of osmostress and osmoprotection on cellular physiology. To measure absolute protein abundances by mass spectrometry, a targeted approach (SRM –single reaction monitoring) using stable heavy isotope labeled artificial standard proteins known as QconCATs was optimized and implemented in the current study. The SRM technique in combination with QconCAT provided absolute quantitative data with high dynamic range for the 45 targeted CCM proteins. Transcriptome data was obtained from microarray analysis. The resulting data were integrated with the other omics data sets obtained by metabolome and flux analysis. As part of a joint study conducted by the BaCell-SysMO and BaSysBio consortia which aimed for the genome wide mapping of transcription units and previously unannotated RNAs of B. subtilis by means of tiling array hybridizations, mRNA samples from growth at high and low temperatures (51°C and 16°C) and in the presence of 1.2 M NaCl, shake flask experiments during transition from exponential growth to the stationary phase, and high density batch fermentation. Time course analysis of B. subtilis transitioning from exponential to stationary phase was investigated by high cell density fed-batch fermentation (glucose limitation) and batch fermentation (glucose exhaustion) with glucose as a limiting factor. A multi-omics analysis of the CCM for the batch fermentation was performed and the time course data was integrated and visualized. In conclusion, pathway based multi-omics data were generated, integrated and visualized as a prerequisite for systems biology approaches and for a better understanding of the complex adaptational responses of B. subtilis.